Model for systemic iron distribution and homeostasis in WT vs Pfn2^−/−mice. Pfn2 KO mice exhibit brain iron accumulation and depletion of liver iron stores with normal hematological parameters. Brain iron overload can be attributed to an increase in transferrin-transferrin receptor endocytosis (Tf-Fe³⁺-TfR1) because of the lack of Pfn2 that negatively regulates this process. Although in WT mice erythropoiesis is supported mainly by liver but also splenic iron, in Pfn2^−/− mice erythropoiesis is supported exclusively by the spleen, where we have detected a substantial increase in ferroportin (Fpn1) production. In Pfn2^−/− mice hepcidin (Hamp1), production in liver is inappropriately normal despite low-iron levels, which should downregulate hepcidin production in order to increase dietary iron absorption and restore liver iron content. Hepcidin inappropriately normal levels in liver of Pfn2^−/−mice are caused by a mild increase in the release of Il6 proinflammatory cytokine that can overrule opposite inhibitory signals.